Pancreatic adenocarcinoma is a devastating disease whose treatment represents a major area of unmet medical need today. Three well recognized characteristics of pancreatic cancer are KRAS mutation early in the disease, extensive fibroinflammation (desmoplasia) leading to decreased blood flow and poor drug delivery, and high levels of tumor hypoxia. We have identified a novel mechanism linking these characteristics that is initiated by KRAS mutation, and maintained and amplified through a self perpetuating cycle of hypoxia, increased HIF-1a, hedgehog signaling, desmoplasia and more hypoxia. Our preliminary studies show a critical interaction between pancreatic cancer cells and the tumor stroma in this process whereby hypoxia of the cancer cells leads to increased HIF-1a and the production of hedgehog ligand, and then formation by stroma fibroblasts in response to hedgehog ligand of fibrous tissue components, thus further increasing the hypoxic stress on the cancer cell. In support of this mechanism we show that elevated tumor HIF-1a and stroma sonic hedgehog ligand are markers of decreased patient survival in pancreatic cancer. In or studies we will investigate the mechanism(s) of the interaction between the pancreatic cancer cell and its stroma leading to desmoplasia, tumor growth and metastasis. Specifically will investigating the role of hypoxia in inhibiting pancreatic cancer cell autocrine hedgehog signaling, and in promoting stroma hedgehog signaling and indirect stimulation of cancer cell growth. We will also investigate the role of the stroma response to hypoxia in limiting the effectiveness of radiation as is currently used for therapy of locally advanced pancreatic cancer. With the information derived we will identify new targets and approaches for more effectively treating pancreatic cancer. We will also exploit a new pathway we have identified that regulates the HIF-1a response of the pancreatic cancer cell to hypoxia to develop novel small molecule inhibitors that can break the tumor cell hypoxia/stroma desmoplasia cycle leading to new and more effective ways of treating pancreatic cancer. The studies are innovative in providing a novel mechanism that explains the high levels of hypoxia and desmoplasia seen in pancreatic cancer leading to decreased patient survival. It provides a new paradigm challenging the view that all pancreatic cancer is a disease of KRAS oncogene addiction. Rather, we propose that while initiated by a mutation of KRAS, for some pancreatic cancers progression is thereafter self sustaining through the cycle of hypoxia, hedgehog signaling and desmoplasia. Finally, we have identified and validated a novel target for small molecule drug development that will allow us to break the cycle of hypoxia and desmoplasia in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease with very few patients surviving more than a year from diagnosis. Characteristics of pancreatic cancer are very large amounts of fibrous tissue which restricts blood flow, causing tumor hypoxia and inhibiting the ability of cancer drugs to reach the tumor. We now show that hypoxia leads to an increase in fibrous tissue and thus more hypoxia, by a pathway that is associated with decreased patient survival. Understanding this pathway will lead to new targets for cancer drugs that can be used in combination with other drugs or radiation to more effectively treat pancreatic cancer.